Prostaglandin synthetase (PGS), an enzyme present in many mammalian cell types has recently been shown to oxidize xenobiotic compounds to toxic and mutagenic metabolites in much the same manner as the more well known cytochrome P-450 system. Since the distribution of PGS in body tissues is different from that of cytochrome P-450, the metabolic activation of xenobiotics by PGS may explain some of the toxic and carcinogenic effects of compounds in tissues that have little or no cytochrome P-450. In this connection, it has recently been shown that butylated hycroxy toluene (BHT), a phenolic food additive antioxidant consumed in significant quantities by humans, causes toxic necrosis of Type I alveolar cells in lungs of mice. Furthermore, BHT also acts as a tumor promoter when given in conjunction with several known carcinogens in mouse lung. It is our hypothesis that BHT is converted to reactive products by the PGS present in the lung. In turn, these reactive metabolites of BHT are capable of causing these harmful effects in the lung. Thus, this proposal seeks to demonstrate that BHT can be metabolized to reactive mutagenic products by the PGS present in lung tissues. Such a reaction may be responsible for the observed pulmonary toxicity of BHT in mice and potentially in humans. Thus, the implications of this study would include; (1) The ingestion of large quantities of BHT and related phenolic food antioxidants by consumers or the exposure of workers to high doses of BHT might lead to an increased risk of alveolar Type I cell toxicity. (2) Since hyperoxia increases the activity of PGS, patients requiring such therapy are particularly susceptible to the BHT-oxygen toxicity. (3) Other tissues or cell types with a high content of PGS might also be susceptible to BHT toxicity. These include the reproductive organs (i.e. uterus), the macrophages and other cells of the immune system.